Thiazoles



United States Patent 3,055,240 Patented Nov. 20, 1962 THIAZOLES Miklos Bodanszky, Princeton, and John T. Sheehan, Middlesex, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virgrma No Drawing. Original appiication Aug. 3, 1960, Ser. No. 47,129, now Patent No. 3,640,054, dated June 19, 1962. Divided and this application Sept. 12, 1961, Ser. No.

3 Claims. (Cl. 260-302) of the formula NH: NI' C [ilhnonrorn HOOC- and salts thereof. Since the thiazolecarboxylic acid contains both basic (i.e. amino) groups and carboxylic acid groups it is amphoteric in nature and thus forms salts with acids and bases. Although any acid or base may be used in preparing the salts, the preferred acids are mineral acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. The preferred bases are ammonium hydroxide, alkali metal hydroxides (e.g., potassium hydroxide and sodium hydroxide) and alkaline earth metal hydroxides (e.g., calcium hydroxide). In addition organic acids, such as tartaric, citric and acetic acid, and organic bases such as alkyla-mines, can be used.

The new thiazolecarboxylic acid of this invention (as well as its salts) is useful as a precursor in the microbial preparation of the antibiotic thiostrepton. For this purpose it is added at a concentration greater than about 0.001% (w./v.) to a nutrient medium containing a source of carbon and energy, a source of assimilable nitrogen and a source of assimilable sulfur (such as that described in U.S. patent application, Serial No. 491,392, filed March 1, 1955, and now US. Patent No. 2,982,689, granted May 2, 1961) when culturing Streptomyces azureus (Waksman Collection No. 3705, Institute of Microbiology, New Brunswick, New Jersey) for the production of thiostrepton.

The final products of this invention are prepared by a series of reactions using as the initial reactant succinaldehyde. These reactions are shown schematically by the following equations. In these equations, R is a hydro carbon radical of less than ten carbon atoms, such as lower alkyl (e.g., methyl, ethyl, propyl, butyl and hexyl), aryl (e.g., phenyl, p-tolyl and o,p-xylyl), aralkyl (e.g., atolyl, phenethyl and 2-phenyl-propyl), and cycloalkyl (e.g., cyclopentyl and cyclohexyl); and R is a saturated hydrocarbon radical of less than ten carbon atoms, such as lower alkyl (e.g., methyl, ethyl, propyl and butyl). Each of the intermediates formed is a new compound of this invention. In addition to their use as intermediates, Compounds IV and V can also be used as precursors in the production of thiostrepton.

or (RCOhO A I. R=phenyl B H. R=pheny1 aoooonontornonooon u F N COOR KOH To prepare Compounds A, succinaldehyde is interacted with a cyanide, such as an alkali metal cyanide (e.g., potassium cyanide), and an acylating agent of either the formula RCOX or (RCO) O, wherein R is as hereinbefore defined, and X is a halide, preferably chloride. The reaction is conducted in an aqueous medium preferably in the cold, and results in the preparation of the two isomers of the diesters of 2,5-dihydroxyhexanedinitrile. In compounds A, the acid moiety of the ester is one corresponding to the acylating agent used.

To prepare Compounds B, either of the isomers of Compound A is treated with hydrogen sulfide, the reaction preferably being conducted under basic conditions. The reaction results in the preparation of Compounds B, the diesters of 2,5-dihydroxydithiohexanediamide, wherein the acid moiety of the ester corresponds to the acylating agent used in the first step of the process.

Compounds B are then condensed with an ester of halopyruvic acid of the formula: XCH COCOOR, wherein X is halo, perferably bromo, and R is as hereinbefore defined. The reaction is preferably conducted in an organic solvent at an elevated temperature, such as the reflux temeprature of the solvent, and results in the preparation of Compounds C, wherein R and R are as hereinbefore defined.

Compounds C are then hydrolyzed in the usual manner, as by treatment with a base, such as an alkali metal hydroxide (e.g., potassium hydroxide) to yield Compound IV, 2,2-(1,4 dihydroxytetramethylene)bis-(4- thiazolecarboxylic acid).

Compound IV is then oxidized by treatment with sodium dichromate to give Compound V, 2,2-succinylbis (4- thiazolecarboxylic acid).

Compound V is then treated with ammonium formate at an elevated temperature and the resulting formyl derivative hydrolyzed, as by treatment with a mineral acid to yield one of the final compounds of this invention, Compound VI, 2,2-(1,4 diaminotetramethylene)bis(4- thiazolecarboxylic acid) which can be converted to a salt in the usual manner by treatment with the desired acid or base.

COOH

i N NCOOH 3 The following examples illustrate the processes of this invention (all temperatures being in centigrade):

EXAMPLE 1 Benzoic Acid, Diester with 2,5-Dihydrxyhexanedinitrile A mixture of 30 g. of succinaldehyde, 750 g. of cracked ice, 44 g. of potassium cyanide and 94 g. (78 ml.) of benzoyl chloride is stirred for 1 hour. A milky semisolid separates from the reaction mixture. The mixture is filtered by suction, and the white solid residue washed with water to give on drying about 15 g. Solid I. The original filtrate of the reaction mixture is extracted four times with 250 ml. portions of chloroform and the combined chloroform extract washed first with a solution containing 60 g. of sodium bicarbonate in 750 ml. of water and finally with three portions of 250 ml. of water. The chloroform extract is dried over anhydrous magnesium sulfate and after removing the latter and evaporating the solvent a residue of about 62 g. of heavy liquid remained. This residue on treatment with several volumes of hexane gives about 19 g. of Solid II.

Solids I and II are separately treated with ether, from which extracts benzoic acid is recovered. The ether insoluble materials are treated with toluene on the steam bath and from these extracts a material, M.P. about 134- 136, separates.

Analysis.Calcd for C H N O C, 68.96; H, 4.63; N, 8.04. Found: C, 68.89; H, 4.60; N, 7.93.

The toluene matrials are then treated with dimethylformamide on the steam bath and solution is complete. On cooling a crystalline product melting at about 214- 216 separates.

Analysis.-Found: C, 68.96; H, 4.81; N, 8.10.

The infrared spectra of both compounds are substantially the same.

EXAMPLE 2 Benzoic Acid, Diester with 2,5-Dihydroxydilhiohexanediamide (II) Into a solution of 4.6 g. of the lower melting dinitrile obtained in Example 1 in 25 ml. of dimethylformamide containing 0.3 ml. of triethanolamine is bubbled hydrogen sulfide for six hours. After the addition of gas, the stoppered mixture is allowed to stand for 24 hours. The mixture is then treated with hexane and enough ethanol to make the mixture homogeneous. On standing a yellow solid slowly separates. Ultimately with scratching and further diluting with hexane and ethanol about 5 g. of product is obtained. The product is crystallized from large volumes of boiling ethanol and melts at about 203-205".

Analysis.Calcd for C H N O S N, 6.73; S, 15.37. Found: N, 6.94; S, 15.40.

EXAMPLE 3 2,2 (1,4-Dihydroxytetramethylene)Bis(4 Thiazolecarboxylic Acid Diethyl Ester, Diester with Benzoic Acid (III) A mixture of 2.5 g. of the dithioamide obtained in Example 2 and 2.5 g. of ethyl bromopyr-uvate in 100 ml. of ethanol is heated under reflux for one and one-half hours on the steam bath. On cooling a solid separates. The solid is filtered off to yield about 2.9 g. of solid, which is crystallized from 100 ml. of boiling ethanol. The product melts at about 144-145.

Analysis.Calcd for C H N O S N, 4.60; S, 10.52. Found: N, 4.68; S, 10.61.

EXAMPLE 4 2,2 (1 ,4-Dihydr0xytetramethylene)Bis(4 Thiazolecarboxylic Acid) (IV) 2.1 g. of the ester obtained in Example 3 is suspended in 50 ml. of absolute ethanol and 0.76 g. of potassium hydroxide in 5 ml. of absolute ethanol is added. While stirring at room temperature solution occurs within onehalf hour. The mixture is allowed to stand at room temperature overnight during which time a solid separates out. The insoluble material is filtered off and washed with ethanol. It is dissolved in 10 ml. of water and the aqueous solution then washed with ether and then acidi fied with 1N hydrochloric acid. From the acid solution a precipitate slowly formed which is filtered off, washed with water, and air dried to give about 1.0 g. of product,- M.P. about 235-240". From the original mother liquor on evaporation a residue of about 1.6 g. of product is obtained. The residue is dissolved in 10 ml. of Water and after washing the aqueous solution with ether, the aqueous solution is acidified with hydrochloric acid and the preciph tate which forms filtered off. This material is benzoic acid. From this and the previous acid solution however, on cooling and standing about 0.2 g. additional product separates. crystallized from boiling water, this compound separates out with one mole of water of crystallization which is lost on drying at The compound, 2,2 (1,4 dihydroxytetramethylene)bis(4-thiazolecarboxylic acid) melts at about 240-242" (dec.).

Analysis.-Calcd for C H N O S C, 41.87; H, 3.51. Found: C, 4201;1-1, 3.95.

EXAMPLE 5 2,2-Succinyl Bis(4Thiaz0lecarb0xylic Acid) (V) 600 mg. of the diol acid obtained in Example 4 is suspended in 15 ml. of glacial acetic acid distilled from chromium trioxide, and 500 mg. of sodium dichromate in one-half a cubic centimeter of water is added to the suspension. The whole is kept at 100 for 2 hours. On cooling an insoluble material settles out. This material is filtered off and washed with a large amount of water and some dilute acetic acid. It Weighs about 400 mg. After crystallization from dimethylformamide the 2,2- succinyl bis(4-thiazolecarboxylic acid) has a M.P. of about 284-286 (dec.).

Analysis.Calcd for C H N O S C, 42.36; H, 2.37. Found: C, 42.52; H, 2.90.

EXAMPLE 6 2,2-(1,4-Diaminotelramethylene)Bis-(4-Tltia20le carboxylic Acid) (VI) 100 mg. of the diketo acid obtained in Example 5 is intimately mixed with 2.0 g. of ammonium formate in a Claisen type distilling flask. The flask is heated in an oil bath at an internal temperature of -155 until the initial foaming reaction subsides. The internal temperature is then gradually raised to -190" where it is kept for 3 hours. On cooling the residue is taken up in 25 ml. of water and any insoluble material removed via filtration. The filtrate is acidified with hydrochloric acid whereupon a precipitate separates out. It is filtered off and washed with water to yield a mixture of formyl derivatives. This mixture is heated under reflux with 5 ml. of concentrated hydrochloric acid for an hour. Hydrolysis proceeds and the mixture becomes homogeneous. On evaporation the residue obtained is dissolved in water from which VI slowly separates. It melts at about 235-237 (dec.). Calcd for C H O N S C, 42.1; H, 4.12; N, 16.4; S, 18.7. Found: C, 42.5; H, 4.29; N, 16.4; S, 18.8. On Whatman No. 1 paper in a system of n-butanol-acetic acid-water '(4:1:1) the acid moves faster than cystine, RF 0.0080.10.

acid. The dihydrochloride salt which forms slowly separates from solution and is removed by filtration.

2,2'- (1 ,4-Diaminotetram ethylene)Bis 4 -Thiaz0lecarboxylic Acid), Ammonium Salt 30 mg. of 2,2'-(1,4-diaminotetramethylene)bis(4-thiazolecarboxylic acid) is dissolved in an excess of ammonium hydroxide. Evaporation of the solvent yields the ammonium salt.

The invention may be variously otherwise embodied Within the scope of the appended claims.

What is claimed is:

l. The diester of 2,2'-(l,4-dihydroxytetramethylene) bis(4-thiazolecarboxylic acid) di(lower alkyl) ester with a hydrocarbon carboxylic acid of less than eleven carbon atoms.

2. The diester of 2,2-(l,4-dihydroxytetramethylene) bis(4-thiazolecarboxylic acid diethyl ester) with benzoic acid.

3. 2,2 (1,4 dihydroxytetramethylene)bis(4-thiaz0lecarboxylic acid).

6 References Cited in the file of this patent UNITED STATES PATENTS 2,731,489 Stansbury et al. Jan. 17, 1956 2,816,130 Selcer et al. Dec. 10, 1957 2,840,594 Coates et al June 24, 1958 2,853,512 Isler et a1 Sept. 23, 1958 2,937,196 Kordak et al May 17, 1960 2,961,446 Harman et al. Nov. 22, 1960 3,002,977 DAmico Oct. 3, 1961 FOREIGN PATENTS 247,990 Switzerland Jan. 3, 1948 OTHER REFERENCES Chem. Abstracts, volume 47, column 

1. THE DIESTER OF 2.2''-(1,4-DIHYDROXYTETRAMETHYLENE) BIS(4-THIAZOLECARBOXYLIC ACID) DI(LOWER ALKYL) ESTER WITH A HYDROCARBON CARBOXYLIC ACID OF LESS THAN ELEVEN CARBON ATOMS,
 3. 2,2''- (1,4- DIHYDROXYTETRAMETHYLENE) BIS(4-THIAZOLECARBOXYLIC ACID). 